Obesity, a chronic metabolic disorder, results from an imbalance between energy intake and energy expenditure. Body fat stores and energy balance are under control of the sympathetic nervous system (SNS). The SNS stimulates lipolysis in adipose cells and thermogenesis in skeletal muscle via activation of adrenergic receptors. Until recently, only b1 and b2-adrenergic receptors were recognized as functionally active in humans. However, it is now clear that a b3-adrenergic receptor is involved in control of energy metabolism and possibly, in the pathogenesis of obesity. A mutation in the b3 AR gene has been shown in several ethnic populations. Individuals who are homozygous for the mutation are characterized by low basal metabolic rate, higher body mass index and earlier onset of type 2 diabetes. A recent study in young healthy male Danes found an association of obesity and decreased insulin sensitivity with homozygosity for the mutation. Although the data is very tantalizing, the role of the b3 AR in the regulation of weight and insulin sensitivity in humans remains enigmatic. AIM 1: To determine in a prospective study whether women who are homozygous for the W64R /3 AR mutation have more severe insulin resistance when compared to women who are heterozygous or wild type homozygotes, independent of obesity. Hypothesis 1. When reduced to ideal body weight, women who are homozygous for the W64R /3 AR mutation will have a more severe degree of insulin resistance (lower M value) when compared to heterozygous women and more so than those homozygous for the wild type gene. To accomplish this objective 36 post-menopausal (50 yr.), obese women who are homozygous for the W64R /3 AR mutation (MM), heterozygous (MN), or homozygous normal (NN) will be weight reduced to near ideal body weight. Characterization for insulin sensitivity will be accomplished with the clamp method before and after achieving weight reduction. We hypothesize that differences in insulin sensitivity, otherwise confounded by the obese state, will be unveiled among the 3 groups. These studies will help define the role of the W64R /3 AR mutation in the genesis of insulin resistance in humans.